Unlocking Iridium Chemical Space for Antibiotic Discovery through One-Pot Combinatorial Synthesis in a Direct-to-Biology Approach

Abstract Antibacterial resistance continues to drive the need for exploring novel chemical spaces beyond conventional organic scaffolds. Metal-based compounds have emerged as a promising class of antibiotic candidates, demonstrating high hit rates against priority bacterial pathogens without exhibiting increased toxicity compared to purely organic molecules. Here, we report a one-pot, three-component combinatorial strategy for the synthesis of piano-stool Ir(III) cyclopentadienyl Schiff-base complexes as potential antibacterial agents. Using 15 picolinaldehydes (A–O), 24 amines (1–24), and four Cp/Cp* iridium precursors (Cp1–4), a library of 1440 complexes was generated and screened directly from crude reaction mixtures in a direct-to-biology approach. Biological screening revealed pronounced activity against Gram-positive Staphylococcus aureus, particularly for biphenyl-substituted Cp (Cp2) complexes, while no activity was observed against Gram-negative bacteria. A subset of the compounds exhibited potent and selective antibacterial activity with low mammalian cell toxicity. Dose-response validation identified 4 promising hit candidates, of which Ir15 displayed low-micromolar activity against a panel of Gram-positive pathogens, limited hemolysis, and moderate cytotoxicity. Initial mechanistic studies indicate that Ir15 acts through a membrane-associated mode of action involving mild membrane depolarization without large pore formation, alongside changes in nucleoid morphology. Overall, this work establishes Ir(III)Cp Schiff-base complexes as a modular antibacterial platform and identifies Ir15 as a promising lead compound for further optimization.